This invention relates to a method of making a controlled release product from an interpolymer complex and an active agent, to a controlled release product comprising an interpolymer complex having an active agent embedded therein, and to the use of an interpolymer complex as a controlled release matrix for an active agent.
The formation of physical polymer networks by interpolymer complexation is well known [see E Tsuchida & K Abe. Interactions between Macromolecules in Solution and Intermacromolecular Complexes, Springer-Verlag, New York, 1982 and E Tsuchida in J.M.S.--Pure Appl. Chem. A31(1) (1994) 1-15]. Interpolymer complexes have been used in medical applications such as permeable contact lenses, permeable wound dressings, corneal implants, vascular grafts, coatings for prosthetic devices, membranes and components for artificial kidneys and blood oxygenators [M K Vogel, R A Cross & H J Bixier J. Macromol. Sci. Chem. A4(3) (1970) 675-692].
As discussed by Scranton et al [Polyelectrolyte Gels. Properties. Preparations and Applications, ACS Symposium Series 480, 1992], interpolymer complexes are formed by the association of two or more complementary polymers, and may arise from electrostatic forces, hydrophobic interactions, hydrogen bonding, van der Waals forces or combinations of these interactions. Due to the long-chain structure of the polymers, once a pair of complementary repeating units associate to form a segmental complex, many other units may readily associate without a significant loss of translational degrees of freedom. Therefore the complexation process is cooperative, and stable interpolymer complexes may form even if the segmental interaction energy is relatively small. The formation of complexes may strongly affect the solubility, rheology, conductivity and turbidity of polymer solutions. Similarly, the mechanical properties, permeability and electrical conductivity of the polymeric systems may be greatly affected by complexation.
Tanaka [Polyelectrolyte Gels, Properties, Preparation and Applications, ACS Symposium Series, 1992] classified the assemblies in biological systems into four fundamental attractive interactions, namely: Electrostatic attraction, Hydrogen bonding, Hydrophobic interaction and van der Waals interaction. ##STR1##
We have shown previously [SA patent 93/4104] how two water-soluble polymers may be converted into a water-insoluble interpolymer complex (at.about.neutral pH) with a specific molecular/aggregate assembly by purely mixing them in the presence of specific solvents. Unlike covalent polymer networks, interpolymer complexes are solvent reversible. Table 1 illustrates the latter in terms of aqueous solubility.
TABLE 1 Solubility of interpolymer complexes (Adapted from Tsuchida) Interpolymer complex Solubility in aqueous media Polyelecrolyte complex Strong polyacid-Strong polybase Not soluble in water (soluble in specific ternary solvents) Strong polyacid-Weak polybase High pH Weak polyacid-Strong polybase Low pH Weak polyacid-Weak polybase High and Low pH Hydrogen-bonding complex High pH. DMSO
Kono et al [J. Appl. Pol. Sci. 59 (1996) 687-693] showed that the permeability of a weak polyacid-weak polybase polyelectrolyte membrane follows similar behaviour to that of solubility as shown in Table 1, i.e., high permeability at low and high pH.
Interpolymer complexes between chitosan and pectin or gum acacia have been applied to controlled release by Meshali et al [Int. J. Phar. 89 (1993) 177-181]. They prepared the interpolymer complexes in solution, separated the precipitate from the solution and dried it in an oven. They concluded that the physical mixture of the polymers as opposed to the interpolymer complex, displayed the most efficient sustained release.
Interpolymer complexes are characterized by valuable properties, namely: biological compatibility, hemocompatibility and low toxicity [A V Kharenko & V A Kemenova Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 22 (1995) 232-233]. Kharenko et al prepared interpolymer complexes from poly(methacrylic acid) and poly(ethylene glycol) and evaluated their use as a matrix for oral controlled-release formulations, particularly for theophylline. It is stated that the interpolymer complex is formed by hydrogen bonding of the carboxylic protons of PMA to the ether oxygens of PEG. No further description of the manufacture of the controlled release system is given.
In Japanese patent 4-312522, a method for the manufacture of a slow release tablet is given. Hydroxypropylmethylcellulose (HPMC) is suspended in hot water. Tannic acid, an acrylic acid-methylmethacrylate-dimethyl aminoethyl methacrylate polymer or a methacrylic acid-acrylic acid ester copolymer is added. The constituent which is obtained by atomization drying is compressed together with the primary medicinal compound. The slow release is achieved by the viscosity of the HPMC and by coating the tablet with a polymer. There is no mention of the formation of an interpolymer complex or embedding of an active agent therein.
Smith et al [Ind. Eng. Chem. 51(11) (1959) 1361-1364] showed how complexation inhibitors may be utilized to re-solubilize interpolymer complexes between poly(acrylic acid) and poly(ethylene oxide). They suggested the use of hydrogen bonding solvents amongst others for this purpose as they suggested these would compete for the hydrogen bonding sites of the respective polymers.
Injectable formulations have been prepared from interpolymer complexes which are stabilized in solution by a complex solubilizer [WO 95/35093]. A pharmaceutical composition including a therapeutic agent and a sustained-release delivery vehicle is disclosed. The delivery vehicle comprises a solution of at least one pharmaceutically acceptable polyacid and at least one pharmaceutically water-soluble, non-ionic polymer, the polyacid and non-ionic polymer forming a stable insoluble interpolymer complex in water at acidic pH, in an aqueous solvent including a pharmaceutically acceptable complex solubilizer, the amount of solubilizer being effective to solubilize the insoluble interpolymer complex. The pharmaceutical composition is intended for injection.
Dangprasirt et al [Drug Dev. & Ind. Pharm. 21(20) (1995) 2323-2337] disclose that diclofenac sodium controlled release solid dispersions were prepared by spray drying using ethylcellulose, methacrylic acid copolymer (Eudragit), chitosan, hydroxypropyl methylcellulose and carbomer as single carriers and ethylcellulose--chitosan as combined carriers. Among solid dispersions of 3:1 drug:single carrier, the system containing chitosan exhibited the slowest dissolution. Combined carriers of ethylcellulose-chitosan exhibited more dissolution retarding effect than single carrier of ethylcellulose or chitosan.
Herzfeldt et al [Pharmazeurische Zeitung 128(29) (1983) 1589-1592] show that some indomethacin-polymer additive-mixtures have been spray dried by a laboratory spray dryer. The spray dried products were investigated as to their technological behaviour and their dissolution rate properties in relation to the source substance. These investigations resulted in an optimised technological behaviour by spray drying indomethacin without additives but also by spray drying in the presence of cationic polyacrylate. The rapid dissolution rate of the source substance is decreased by spray drying indomethacin in mixtures with methylcellulose and cationic polyacrylate. The spray dried products with polyvinylpyrrolidone including the addition of sodium lauryl sulphate consists of nano- and microcapsules. There is no mention of the formation of interpolymer complexes.
A need exists for novel controlled release products for oral administration, where the release of the active agent from the product can be controlled over a range of release rate and profiles and at different pHs, made by methods which differ from the existing methods described above, which methods provide various advantages such as cost reduction and enhancement of up-scaleability of the methods.